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Райдапт — Rydapt (мидостаурин)

Райдапт — Rydapt (мидостаурин)

Препарат Райдапт – это современное противоопухолевое средство, показанное для лечения впервые диагностированного острого миелоидного лейкоза (ОМЛ) с FLT3-мутацией, применяется в сочетании с даунорубицином и цитарабином. Лекарство Райдапт может использоваться только в том случае, если ваша опухоль имеет специфический генетический маркер, для которого ваш врач будет тестировать. Основное действующее вещество — мидостаурин.

Описание

Препарат Райдапт – это современное противоопухолевое средство, показанное для лечения впервые диагностированного острого миелоидного лейкоза (ОМЛ) с FLT3-мутацией, применяется в сочетании с даунорубицином и цитарабином. Лекарство Райдапт может использоваться только в том случае, если ваша опухоль имеет специфический генетический маркер, для которого ваш врач будет тестировать. Основное действующее вещество — мидостаурин.

Препарат Райдапт также используется для лечения некоторых редких заболеваний крови, включая системный мастоцитоз с лейкемией тучных клеток или других видов рака, поражающих кровь, костный мозг или лимфатическую ткань.

Показания к применению

  • острый миелоидный лейкоз (ОМЛ) положительный по FLT3-мутации у взрослых пациентов, в сочетании с даунорубицином и цитарабином
  •  агрессивного системного мастоцитоза,
  • системного мастоцитоза c ассоциированным гематологическим новообразованием
  • тучноклеточного лейкоза.

Состав Райдапт

1 капсула содержит:

  • действующее вещество: мидостаурин 25 мг;
  • дополнительные вещества: макрогола глицерилгидроксистеарат, этанол, макрогол 400, моноглицериды, альфа-токоферол, ди- и триглицериды кукурузного масла.
  • оболочка капсулы: желатин, глицерол 85 процентов, титана диоксид (Е171), краситель железа оксид желтый, краситель железа оксид красный, вода;
  • состав красных чернил : кармин красный, пропиленгликоль, гипромеллоза 2910.

Фармакодинамика

Лекарственное средство Райдапт блокирует множество рецепторных тирозинкиназ, включая FLT3 и KIT киназы, блокирует сигнал рецептора FLT3 и индуцирует остановку клеточного цикла и апоптоз в лейкозных клетках, экспрессирующих мутантные рецепторы TKD и ITD или сверхэкспрессирующих рецепторы дикого типа. Блокирование дикого D816V, и мутантного гена KIT ведет к вмешательству в передачу аберрантного сигнала KIT киназой, также подавляет пролиферацию, выживаемость тучных клеток и высвобождение гистамина.

Кроме того, он подавляет и другие рецепторные тирозинкиназы, такие как VEGFR2 или PDGFR , а также представителей семейства серинтреониновых киназ – протеинкиназы С (РКС). Препарат Райдапт связывается с каталитическим доменом таких киназ и подавляет митогенные сигналы факторов роста, что ведет к остановке их роста. Взаимодействие со многими химиотерапевтическими лекарственными препаратами (за исключением метотрексата) приводила к синергическому торможению роста в FLT3-ITD экспрессирующих клеточных линиях острого миелоидного лейкоза (ОМЛ).

Препарат Райдапт является ингибитором с высокой степенью сродства к рецепторной тирозинкиназе FLT3 (Kd 11 нМ) и в равной степени активен в отношении TKD — и ITD- мутантного FLT3.

К рецепторной тирозинкиназе дикого типа KIT константа аффинности мидостаурин была определена как 220 нМ, а к D816V мутантному гену – 7,7 нМ.

На моделях мыши и человека идентифицированы два основных метаболита. В исследованиях пролиферации с экспрессирующими FLT3-ITD клетками. CGP62221 показал аналогичную эффективность по сравнению с исходным соединением, тогда как CGP52421 был примерно в 10 раз менее активным.

Кардиоэлектрофизиология

В исследовании с участием 192 здоровых добровольцев, принимавших препарат Райдапт в дозировке 75 мг дважды в день, не было обнаружено клинически значимого удлинения интервала QT, обусловленного мидостаурином и CGP62221. Вместе с тем, длительность исследования не была достаточной для оценки удлинения корригированного интервала QT (QTc), вызванной метаболитом CGP5242.

Фармакокинетика

Абсорбция

После приема внутрь абсорбция мидостаурина происходит быстро, при этом время достижения максимальной концентрации в плазме крови (Тmax) общей радиоактивности определяется через 1-3 часа после приема дозировки. Степень абсорбции мидостаурина (площадь под кривой «концентрация – время» (AUC)) у здоровых лиц была увеличена в среднем на 22 процента при приеме мидостаурина совместно со стандартной пищей и, в среднем, на 59 процентов при его приеме с пищей с высоким содержанием жиров. Максимальная концентрация мидостаурина (Сmax) снижалась на 20 процентов при приеме со стандартной пищей и на 27 процентов – с пищей с высоким содержанием жиров или натощак. Время до пиковой концентрации также удлинялось в присутствии стандартной пищи или пищи с высоким содержанием жиров (медиана Тmax 2,5-3 часа). В клинических исследованиях препарат принимался совместно с легкой пищей, для снижения проявлений тошноты и рвоты. Пациентам рекомендуется принимать мидостаурин совместно с пищей.

Распределение Райдапт

Препарат Райдапт имеет высокое среднее геометрическое кажущегося объема распределения в терминальной фазе (Vz/F) – 95,2 л. Мидостаурин и его метаболиты распределяются преимущественно в плазме крови. По результатам данных мидостаурин связывается с белками плазмы крови in vitro ( более 98 процентов), главным образом, с альфа-1-кислотным гликопротеином.

Биотрансформация/метаболизм

Мидостаурин в основном метаболизируется изоферментом CYP3A4. Активные метаболиты CGP62221 и CGP52421 составляют 27,7±2,7 процентов и 37,97±6,6 процентов соответственно от общей экспозиции в плазме крови.

Основные пути метаболизма у человека, приводящие к образованию 16-ти метаболитов — окисление в пирролидининовом кольце, О-деметилирование, окисление в бензольном кольце, гидролиз амидной связи и N-деметилирование. Изоферменты CYP3A4, CYP3A5, CYP1A1 способны метаболизировать как CGP62221, так и CGP52421.

Элиминация Райдапт

Период полувыведения (Т1/2) составляет 20,9 часов для мидостаурина, 32,3 часа для CGP62221 и 471 час для CGP52421.

Экскреция с калом составляет 78 процентов от дозы, при этом 73 процента от дозировки выделяется в виде метаболитов и 3 процента – в виде неизменного мидостаурина. Только 4 прооцента от дозировки было обнаружено в моче.

16 радиоактивно меченых метаболитов были обнаружены и количественно определены в моче и в кале . В кале преобладающим метаболитом является Р29.6В (26,7 процентов), в моче – Р6В (гиппуриновая кислота).

Линейность / нелинейность Райдапт

После приема однократной дозировки в диапазоне от 25 мг до 100 мг мидостаурин и его метаболиты не показали значительного отклонения от дозопропорциональности. Однако, после приема нескольких дозировок в диапазоне от 50 мг до 225 мг в день, было зафиксировано меньшее увеличение концентрации, чем дозопропорциональное.

После приема внутрь нескольких дозировок мидостаурин продемонстрировал фармакокинетику, зависящую от времени с начальным повышением концентрации в плазме в течение первой недели (пик Cmin), после чего концентрация понижалась до равновесного состояния (примерно через 28 дней). Хотя точный механизм снижения концентрации мидостаурина не известен, предположительно, это связано с индукцией изофермента CYP3A4. Фармакокинетика метаболита CGP62221 продемонстрировала схожую картину. Концентрация метаболита CGP52421 увеличились до 9 раз у больных с ОМЛ по сравнению с мидостаурином после месяца терапии.

Фармакокинетика у особых групп пациентов

Пациенты <18 лет

Эффективность и безопасность у пациентов данной возрастной категории не установлена.

Пациенты ≥65 лет

На основе данных популяционной фармакокинетики статистически значимого влияния возраста на клиренс препарата Райдапт и его активных метаболитов не обнаружено, ожидаемые изменения концентрации не считались клинически значимыми. У больных данной возрастной категории с ОМЛ коррекция дозировки препарата Райдапт не требуется.

Пол

На основе данных популяционной фармакокинетики статистически значимого результата влияния пола на клиренс препарата Райдапт и его активных метаболитов не обнаружено. Ожидаемые изменения концентрации не считались клинически значимыми. Коррекция дозы мидостаурина в зависимости от пола не требуется.

Расовая /Этническая принадлежность

Фармакокинетический профиль представителей европеоидной и негроидной расы не различается. Коррекция дозы мидостаурина по этническому признаку не требуется.

Пациенты с нарушением функции печени

В клиническом исследовании, оценивающем системное воздействие мидостаурина у больных с исходным нарушением функции печени легкой или средней степени тяжести (класс А и В по шкале Чайлд-Пью) и нормальной функцией печени, не выявлено клинически значимого увеличения экспозиции (AUC) по сравнению с больными с нормальной функцией печени. Не требуется коррекция дозы мидостаурина у пациентов с нарушением функции печени легкой или средней степени тяжести .

Не оценивалась фармакокинетика мидостауринау пациентов с нарушениями функции печени тяжелой степени (класс С по шкале Чайлд-Пью).

Пациенты с нарушением функции почек

Коррекция дозировки у пациентов с нарушением функции почек легкой или средней степени тяжести не требуется.

Применение при беременности и кормлении грудью

Беременность

У беременных женщин применение препарата Райдапт может приводить к повреждению плода. Беременные женщины должны быть предупреждены о потенциальном риске для плода. Данные о применении мидостаурина у беременных женщин отсутствуют.

Лактация

Отсутствуют данные о проникновении мидостаурина и его активных метаболитов в грудное молоко человека, об оказываемых влияниях на продукцию грудного молока и детей, получавших такое питание.

По фармакодинамическим (токсикологическим) данным, полученным от исследований на животных, определено проникновении мидостаурина и его активных метаболитов в грудное молоко.

Во время лечения препаратом Райдапт следует прекратить грудное вскармливание и в течение 4 месяцев после окончания лечения.

Фертильность

На основании данных, полученных от исследований на животных, мидостаурин может ухудшать фертильность. Обратимость нарушения фертильности неизвестна.

Женщины с детородным потенциалом

Пациенткам с детородным потенциалом рекомендуется пройти тест на беременность за 7 дней до начала применения препарата Райдапт.

Контрацепция у мужчин и женщин

Во время лечения препаратом Райдапт и в течение 4 месяцев после окончания терапии, пациенты мужского и женского пола, обладающие детородным потенциалом, должны использовать эффективные методы контрацепции

Данных о влиянии препарата Райдапт на эффективность пероральных контрацептивов нет. Однако, пациенткам, принимающим пероральные противозачаточные препараты, следует применять дополнительные барьерные методы контрацепции.

Мужчины, принимающие препарат Райдапт, должны применять презерватив во время полового акта и в течение 4 месяцев после прекращения лечения препаратом Райдапт, для предупреждения возникновения беременности или развития эмбриональных нарушений плода.

Фармацевтические характеристики Райдапт

Ридапт выпускается в форме мягких капсул. Каждая капсула содержит активное вещество мидостаурин в дозировке 25 мг.

Содержимое капсул: раствор от прозрачного до слегка опалесцирующего, от желтого до зеленовато-желтого или до очень темно-желтого, или до очень темно-зеленовато-желтого цвета.

Упаковка, срок годности, условия хранения Райдапт

По 4 капсулы упакованы в блистер из ПА/Ал/ПВХ и фольги алюминиевой. По 7 блистеров упакованы вместе с инструкцией по применению в пачку картонную. Допускается наличие контроля первичного вскрытия. В одной упаковке по 112 таблеток.

Хранят Ридапт при комнатной температуре в условиях невысокой относительной влажности. Беречь от детей. Не применять по истечению срока годности, который указан на упаковке.

Срок годности препарата 2 года. Не применять после истечения срока годности, указанного на упаковке.

 

 

 

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а также можем отправить Райдапт (мидостаурин) по регионам Казахстана: Нур-Султан (Астана), Шымкент, Талдыкорган, Актау и другие.

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